Apolipoprotein E (apoE) is a 299 amino acid protein with multiple biological properties. In addition to its well defined role in cholesterol metabolism, apoE appears to play a singularly important role in human neurological disease. In particular, apoE4, one of the three common human isoforms of this protein, has been associated with increased incidence of developing late-onset familial and sporadic Alzheimer's Disease, and poor neurological outcome in patients with multiple sclerosis, intracranial hemorrhage, and stroke. Recently, there have also been a number of independent observations identifying a robust association between apoE isoform and functional outcome following closed head injury. In this proposal, we will utilize targeted replacement mice expressing the different human apoE isoforms to identify the isoform-specific role of apoE in a murine head injury model that we have recently characterized. Although this model utilizes acute mortality, cerebellar and motor deficits as short-term endpoints, we will also model the neurocognitive dysfunction that is a common clinical long-term consequence of traumatic brain injury. We will specifically test the hypothesis that the endogenous expression of apoE modifies short-term and long-term post-traumatic neurological deficits by modulating glial activation and the CNS inflammatory response in an isoform-specific manner. We will next extend our work demonstrating that small peptides derived from the receptor-binding region of apoE can exert neuroprotective effects in vivo, and may serve as a novel therapeutic strategy to reduce the acute mortality and long term neurocognitive deficits associated with traumatic brain injury. We will use this system to investigate possible pharmacogenomic interactions between the therapeutic apoE peptide and the humanized apoE background in the targeted replacement mice.